Genetic variation at the IL-18-137C>G is associated with poor sepsis prognosis and enhanced inflammatory responses: a
Zhuoji Li1,2, Wanjie Gu1, Lizhen Liu3,4
1Jinan University, Guangzhou, Guangdong, China.
Background:
Sepsis is a life-threatening condition caused by dysregulated immune responses, leading to inflammation, tissue damage, and organ failure. This study investigates the role of the IL-18 rs187238 (-137C>G) polymorphism in sepsis susceptibility, progression, and patient prognosis.
Methods:
A multicenter case-control study was conducted with 784 sepsis patients and 776 healthy controls. The IL-18 rs187238 polymorphism was genotyped using imLDR™ multiplex SNP genotyping method. ELISA and qRT-PCR were used to detect related inflammatory cytokine expression, while functional analysis was performed using dual-luciferase assays to evaluate the impact of the rs187238 variant on IL-18 promoter activity.
Results:
We observed a significant association between the rs187238 polymorphism and 28-day ICU mortality in sepsis patients. The CG/GG genotypes (OR = 1.470, 95% CI = 1.029-2.129, P = 0.037) were more frequently observed in non-survivors compared to survivors, with a notable difference in the frequency of the G allele (OR = 1.534, 95% CI = 1.111-2.133, P = 0.010). Kaplan-Meier survival analysis confirmed that patients with CG/GG genotypes had significantly lower 28-day survival rates compared to those with the CC genotype (P = 0.028). However, no significant differences in genotype and allele frequencies were observed between cases and healthy controls, nor between sepsis and septic shock patients. Sepsis patients with CG/GG genotypes had significantly higher IL-18 levels than those with the CC genotype. Dual-luciferase assays confirmed that the G allele increased IL-18 promoter activity, supporting its genetic influence on IL-18 expression. Additionally, sepsis patients with CG/GG genotypes expressed significantly increased levels of IL-1β, IL-6, and ICAM-1 than those with CC genotype. IL-18 treatment enhanced the expression of IL-1β, IL-6, IL-27, TNF-α, and MCP-1 in THP-1 macrophages upon LPS stimulation. In HUVECs, IL-18 treatment further enhanced LPS-induced IL-6, IL-27, TNF-α, and ICAM-1 expression, while promoting apoptosis and reducing VE-cadherin levels, emphasizing its role in inflammation and endothelial dysfunction in sepsis.
Conclusion:
The IL-18 rs187238 C>G polymorphism is linked to higher IL-18 expression and intensified inflammatory responses, which are associated with poor sepsis prognosis. The sepsis-associated risk rs187238-G allele serves as a potential prognostic biomarker for sepsis-related mortality. Targeting IL-18 or its genetic variations might offer new avenues for sepsis therapy.